A Cross‐Sectional Study Reveals Hormonal Signatures of Smoking‐Related Infertility

Cigarette smoking remains a common modifiable lifestyle risk factor for male infertility, yet the exact mechanisms linking smoking to overall fertility decline are not fully understood. This study investigates how smoking affects sperm quality deterioration and examines the potential role of hormonal pathways in mediating these effects. Robust causal approaches have been utilized to measure both the overall impact of smoking and its hormonal mediation on semen parameters. Additionally, a unidimensional Sperm Quality Index (SQI) has been developed and validated internally, while latent reproductive phenotypes have been analyzed through unsupervised clustering techniques. This observational study involved 104 infertile men, with 52 smokers and 52 nonsmokers. Inverse‐probability‐of‐treatment weighting (IPTW) and augmented IPTW (AIPW) were used to balance 21 baseline covariates. Parallel mediation analysis evaluated four pituitary‐gonadal hormones—follicle‐stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), and testosterone—as mediators of smoking's impact on five key semen parameters: concentration, total count, progressive motility, morphology, and live sperm percentage. Principal component analysis (PCA) was used to create a PCA‐based SQI by combining nine logarithmically transformed, z‐standardized variables. The mediation analysis was also repeated using the SQI. K‐means clustering, using the gap statistic, identified four latent semen–hormone phenotypes. After IPTW, smoking was associated with standardized AIPW average treatment effects (ATEs) of –0.29 to –0.66 standard deviation (SD) across semen parameters (e.g., live sperm % ATE = –0.67, 95% confidence interval (CI) –1.01 to –0.33; morphology ATE = –0.40, 95% CI –0.75 to –0.05). Parallel mediation indicated LH as the principal mediator, explaining 40%–63% of smoking's total effect on individual outcomes. The PCA‐derived SQI explained 65% of semen variance, and smoking's ATE on SQI was –0.44 SD (95% CI –0.80 to –0.07), with 66% mediated via hormones (suppression effect). Clustering revealed four phenotypes: (1) normozoospermic, (2) subclinical endocrinal disruption, (3) intermediate, and (4) severely impaired (high LH, low SQI), with smokers predominating cluster 4 (85% smokers vs. 15% nonsmokers). Cigarette smoking primarily impacts semen quality by disrupting endocrine hormones. The PCA‐based SQI offers a more sensitive overall measure of impairment compared to individual parameters and can serve as a straightforward biomarker for evaluating sperm quality, aiding clinicians in diagnosing male infertility. The characterized phenotypes suggest potential for personalized treatment strategies. These findings emphasize the importance of quitting smoking for fertility treatment and indicate that pituitary‐gonadal hormones could be promising targets for therapy.